Is CD37 p.Ala221Thr (c.661G>A) pathogenic?

CD37 p.Ala221Thr (c.661G>A) is classified Uncertain significance in CD37 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0767); Very rare (popmax 0.00801%, afr).

How common is CD37 p.Ala221Thr (c.661G>A) in the general population?

CD37 p.Ala221Thr (c.661G>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about CD37 p.Ala221Thr (c.661G>A)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

CD37 p.Ala221Thr

c.661G>A · VCV3998245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 3.2, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 4,784 bp · p 0.63 · regional, not allelic
Overall
CADD	16.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,920 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000496% 8/1,613,658 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
East Asian	0.00223%	44,880
European (non-Finnish)	8.48e-05%	1,179,800

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CD37
Protein: p.Ala221Thr
Coding: c.661G>A
MANE Select: NM_001774
Type: single nucleotide variant
Location: chr19:49338913 (GRCh38)
Gene constraint: LOEUF 1.215 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.31

Full CD37 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD37 p.Val44= Benign ★★ same type
CD37 p.Arg112Gly Uncertain significance ★ ⚠ same type
CD37 p.Arg112Pro Uncertain significance ★ ⚠ same type
CD37 p.Arg120Leu Uncertain significance ★ ⚠ same type
CD37 p.Arg281Cys Uncertain significance ★ ⚠ same type
CD37 p.Arg281Ser Uncertain significance ★ ⚠ same type
CD37 p.Asn170Asp Uncertain significance ★ ⚠ same type
CD37 p.Asn275Lys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cd37-p-ala221thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown